Endoparasiticidal agents for voluntary oral ingestion by animals

ABSTRACT

The present invention relates to pharmaceutical presentations for animals which are administered orally and which are accepted readily by the animals (for example dogs, cats and horses), to processes for their preparation and to their use, in particular as endoparasiticides.

The present invention relates to pharmaceutical presentations foranimals which are administered orally and which are accepted readily bythe animals (for example dogs, cats and horses).

To administer drugs orally, it is generally customary, also forveterinary purposes, to preferably use tablets, that is to saycompressed materials of active compound and ancilliary material. Theseare quite unattractive for the animals and are, as a rule, only acceptedreluctantly so that the animal keeper must wrap the tablets in food inorder to administer them. This does not always guarantee that all of themedicament, and thus the correct dose of the medicament, can beadministered.

The palatability of these tablets can be increased for example by addingvarious aromas and flavourings (DE A 196 17 487, WO 95/31963, U.S. Pat.No. 4,851,226). In addition, the shape of the tablet may be altered, forexample into the shape of a bone when used for dogs (U.S. Pat. No.4,857,333). Furthermore, laminated tablets are prepared which containattractants as the outer layer (EP A 320 320, EP A 574 301). The maindisadvantage of these improved tablet systems is that the animal canclearly distinguish them from normal feed, so that complete acceptancecannot be achieved even with these systems.

The melt extrusion into tablets of suitable polymers for oraladministration is known for use in humans, but the acceptance of thesetablets by animals is insufficient owing to their consistency (WO96/29053).

It is known that the extrusion of starch allows a very wide range ofshaped articles to be produced which are employed in particular in thefeeds industry (U.S. Pat. No. 3,899,607). However, the suitability ofthese feeds as carriers for pharmaceutical active compounds is onlylimited since they contain up to 50% meat and thus do not comply withthe rules of a pharmaceutical presentation. However, the acceptance ofthese extrudates is very good, owing to the added meat and the shape.

In contrast, no acceptance was found with pure starch extrudates forpharmaceutical active compounds (EP A 0 118 240, EP A 390 960). Theattraction of feed extrudates depends primarily on the flavouring, butalso decisively on the physical composition [M. Thomas et al, AnimalFeed Science Technology 70 (1998) 59-78].

To make the administration of endoparasiticidal active compounds assimple as possible for the animal keeper, it is therefore desirable toprovide a composition which is accepted readily by the animal.

Surprisingly, there have now been found starch-based extruded shapedarticles as pharmaceutical presentation which act as carriers forpharmaceutical active compounds and are without added meat, but whichare accepted readily by the animals.

Also subject-matter of the present invention is the use of thispharmaceutical presentation as carrier for pharmaceutical activecompounds in veterinary medicine, in particular for endoparasiticidallyactive cyclic depsipeptides, as they are described, for example, inEP-OS 382 173 and DE-A 4 317 432.9; DE-A 4 317 457.4; DE-A 4 317 458.2.

Subject-matter of the present invention are:

-   1. Starch-based extruded shaped articles, characterized in that they    comprise specific aromas, bodying agents and pharmaceutical active    compounds for animals.-   2. Starch-based extruded shaped articles according to Item 1,    characterized in that they contain poultry liver aroma or meat aroma    as aromas.-   3. Starch-based extruded shaped articles according to Item 1,    characterized in that they have a Shore A hardness of 10 to 100.-   4. Starch-based extruded shaped articles according to Items 1 and 2,    characterized in that they contain cyclic depsipeptides composed of    amino acids and hydroxycarboxylic acids as units and having 6 to 30    ring or chain atoms.-   5. Starch-based extruded shaped articles according to Items 1, 2 and    3, characterized in that they have added to them pulverulent    cellulose acetate.-   6. Starch-based extruded shaped articles according to Items 1, 2, 3    and 4, characterized in that they contain further ancilliary    materials such as emulsifiers, humectants and preservatives.-   7. Process for the preparation of starch-based extruded shaped    articles according to Items 1, 2, 3, 4 and 5, characterized in that    the starting materials are mixed and processed at temperatures of    less than 150° C.

Active compounds which are suitable are, in principle, all activecompounds which are suitable for use in veterinary medicine. Especiallysuitable are the active compounds from the class of the depsipeptides,in particular cyclic depsipeptides.

Preferred cyclic depsipeptides are those having 18 to 24 ring atoms, inparticular 24 ring atoms.

The depsipeptides having 18 ring atoms include compounds of the generalformula (I):

in which

-   R¹, R³ and R⁵ independently of one another represent hydrogen,    straight-chain or branched alkyl having up to 8 carbon atoms,    hydroxyalkyl, alkanoyloxyalkyl, alkoxyalkyl, aryloxyalkyl,    mercaptoalkyl, alkylthioalkyl, alkylsulphinylalkyl,    alkylsulphonylalkyl, carboxyalkyl, alkoxycarbonylalkyl,    arylalkoxycarbonylalkyl, carbamoylalkyl, aminoalkyl,    alkylaminoalkyl, dialkylaminoalkyl, guanidinoalkyl which can    optionally be substituted by one or two benzyloxycarbonyl radicals    or by one, two, three or four alkyl radicals, or represent    alkoxycarbonylaminoalkyl,    9-fluorenylmethoxycarbonyl(Fmoc)-aminoalkyl, alkenyl, cycloalkyl,    cycloalkylalkyl and optionally substituted arylalkyl, substituents    which may be mentioned being halogen, hydroxyl, alkyl and alkoxy,-   R², R⁴ and R⁶ independently of one another represent hydrogen,    straight-chain or branched alkyl having up to 8 carbon atoms,    hydroxyalkyl, mercaptoalkyl, alkanoyloxyalkyl, alkoxyalkyl,    aryloxyalkyl, alkylthioalkyl, alkylsulphinylalkyl,    alkylsulphonylalkyl, carboxyalkyl, alkoxycarbonylalkyl,    arylalkoxycarbonylalkyl, carbamoylalkyl, aminoalkyl,    alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonylaminoalkyl,    alkenyl, cycloalkyl, cycloalkylalkyl, optionally substituted aryl or    arylalkyl, substituents which may be mentioned being halogen,    hydroxyl, alkyl, alkyoxy,    -   and their optical isomers and racemates.

Preferred are compounds of the formula (I),

in which

-   R¹, R³ and R⁵ independently of one another represent straight-chain    or branched C₁-C₈-alkyl, in particular methyl, ethyl, propyl,    isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,    isopentyl, sec-pentyl, hexyl, isohexyl, sec-hexyl, heptyl,    isoheptyl, sec-heptyl, tert-heptyl, octyl, isooctyl, sec-octyl,    hydroxy-C₁-C₆-alkyl, in particular hydroxymethyl, 1-hydroxyethyl,    C₁-C₄-alkanoyloxy-C₁-C₆-alkyl, in particular acetoxymethyl,    1-acetoxyethyl, C₁-C₄-alkoxy-C₁-C₆-alkyl, in particular    methoxymethyl, 1-methoxyethyl, aryl-C₁-C₄-alkyloxy-C₁-C₆-alkyl, in    particular benzyloxymethyl, 1-benzyloxyethyl, mercapto-C₁-C₆-alkyl,    in particular mercaptomethyl, C₁-C₄-alkylthio-C₁-C₆-alkyl, in    particular methylthioethyl, C₁-C₄-alkylsulphinyl-C₁-C₆-alkyl, in    particular methylsulphinylethyl, C₁-C₄-alkylsulphonyl-C₁-C₆-alkyl,    in particular methylsulphonylethyl, carboxy-C₁-C₆-alkyl, in    particular carboxymethyl, carboxyethyl,    C₁-C₄-alkoxycarbonyl-C₁-C₆-alkyl, in particular    methoxycarbonylmethyl, ethoxycarbonylethyl,    C₁-C₄-arylalkoxycarbonyl-C₁-C₆-alkyl, in particular    benzyloxycarbonylmethyl, carbamoyl-C₁-C₆-alkyl, in particular    carbamoylmethyl, carbamoylethyl, amino-C₁-C₆-alkyl, in particular    aminopropyl, aminobutyl, C₁-C₄-alkylamino-C₁-C₆-alkyl, in particular    methylaminopropyl, methylaminobutyl, C₁-C₄-dialkylamino-C₁-C₆-alkyl,    in particular dimethylaminopropyl, dimethylaminobutyl,    guanido-C₁-C₆-alkyl, in particular guanidopropyl,    C₁-C₄-alkoxycarbonylamino-C₁-C₆-alkyl, in particular    tert-butoxycarbonylaminopropyl, tert-butoxycarbonylaminobutyl,    9-fluorenyl-methoxycarbonyl(Fmoc)amino-C₁-C₆-alkyl, in particular    9-fluorenylmethoxy-carbonyl(Fmoc)aminopropyl,    9-fluorenylmethoxycarbonyl(Fmoc)aminobutyl, C₂-C₈-alkenyl, in    particular vinyl, allyl, butenyl, C₃-C₇-cycloalkyl, in particular    cyclopentyl, cyclohexyl, cycloheptyl, C₃-C₇-cycloalkyl-C₁-C₄-alkyl,    in particular cyclopentylmethyl, cyclohexylmethyl,    cycloheptylmethyl, phenyl-C₁-C₄-alkyl, in particular phenylmethyl    which can optionally be substituted by radicals from the series    halogen, in particular fluorine, chlorine, bromine or iodine,    hydroxyl, C₁-C₄-alkoxy, in particular methoxy or ethoxy, and    C₁-C₄-alkyl, in particular methyl,-   R², R⁴ and R⁶ independently of one another represent straight-chain    or branched C₁-C₈-alkyl, in particular methyl, ethyl, propyl,    isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,    isopentyl, sec-pentyl, hexyl, isohexyl, sec-hexyl, heptyl,    isoheptyl, sec-heptyl, tert-heptyl, octyl, isooctyl, sec-octyl,    hydroxy-C₁-C₆-alkyl, in particular hydroxymethyl, 1-hydroxyethyl,    C₁-C₄-alkanoyloxy-C₁-C₆-alkyl, in particular acetoxymethyl,    1-acetoxyethyl, C₁-C₄-alkoxy-C₁-C₆-alkyl, in particular    methoxymethyl, 1-methoxyethyl, aryl-C₁-C₄-alkyloxy-C₁-C₆-alkyl, in    particular benzyloxymethyl, 1-benzyloxyethyl, mercapto-C₁-C₆-alkyl,    in particular mercaptomethyl, C₁-C₄-alkylthio-C₁-C₆-alkyl, in    particular methylthioethyl, C₁-C₄-alkylsulphinyl-C₁-C₆-alkyl, in    particular methylsulphinylethyl, C₁-C₄-alkylsulphonyl-C₁-C₆-alkyl,    in particular methylsulphonylethyl, carboxy-C₁-C₆-alkyl, in    particular carboxymethyl, Carboxyethyl,    C₁-C₄-alkoxycarbonyl-C₁-C₆-alkyl, in particular    methoxycarbonylmethyl, ethoxycarbonylethyl,    C₁-C₄-arylalkoxycarbonyl-C₁-C₆-alkyl, in particular    benzyloxycarbonylmethyl, carbamoyl-C₁-C₆-alkyl, in particular    carbamoylmethyl, carbamoylethyl, amino-C₁-C₆-alkyl, in particular    aminopropyl, aminobutyl, C₁-C₄-alkylamino-C₁-C₆-alkyl, in particular    methylaminopropyl, methylaminobutyl, C₁-C₄-dialkylamino-C₁-C₆-alkyl,    in particular dimethylaminopropyl, dimethylaminobutyl,    C₂-C₈-alkenyl, in particular vinyl, allyl, butenyl,    C₃-C₇-cycloalkyl, in particular cyclopentyl, cyclohexyl,    cycloheptyl, C₃-C₇-cycloalkyl-C₁-C₄-alkyl, in particular    cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, phenyl,    phenyl-C₁-C₄-alkyl, in particular phenylmethyl which can optionally    be substituted by radicals from the series halogen, in particular    fluorine, chlorine bromine or iodine, hydroxyl, C₁-C₄-alkoxy, in    particular methoxy or ethoxy, and C₁-C₄-alkyl, in particular methyl,    and their optical isomers and racemates.

Especially preferred are compounds of the formula (I),

in which

-   R¹, R³ and R⁵ independently of one another represent C₁-C₈-alkyl, in    particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl,    sec-butyl, pentyl, isopentyl, sec-pentyl, hexyl, isohexyl,    sec-hexyl, heptyl, isoheptyl, sec-heptyl, octyl, isooctyl,    sec-octyl, hydroxy-C₁-C₆-alkyl, in particular hydroxymethyl,    1-hydroxyethyl, C₁-C₄-alkanoyloxy-C₁-C₆-alkyl, in particular    acetoxymethyl, I-acetoxyethyl, C₁-C₄-alkoxy-C₁-C₆-alkyl, in    particular methoxymethyl, 1-methoxyethyl,    aryl-C₁-C₄-alkyloxy-C₁-C₆-alkyl, in particular benzyloxymethyl,    1-benzyloxyethyl, C₁-C₄-alkoxycarbonylamino-C₁-C₆-alkyl, in    particular tert-butoxycarbonylaminopropyl,    tert-butoxycarbonylaminobutyl, C₂-C₈-alkenyl, in particular vinyl,    allyl, C₃-C₇-cycloalkyl, in particular cyclopentyl, cyclohexyl,    cycloheptyl, C₃-C₇-cycloalkyl-C₁-C₄-alkyl, in particular    cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl,    phenyl-C₁-C₄-alkyl, in particular phenylmethyl which can optionally    be substituted by one or more identical or different radicals from    amongst those stated above,-   R², R⁴ and R⁶ independently of one another represent straight-chain    or branched C₁-C₈-alkyl, in particular methyl, ethyl, propyl,    isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,    isopentyl, sec-pentyl, hexyl, isohexyl, sec-hexyl, heptyl,    isoheptyl, sec-heptyl, tert-heptyl, octyl, isooctyl, sec-octyl,    hydroxy-C₁-C₆-alkyl, in particular hydroxymethyl,    aryl-C₁-C₄-alkyloxy-C₁-C₆-alkyl, in particular benzyloxymethyl,    1-benzyloxyethyl, carboxy-C₁-C₆-alkyl, in particular carboxymethyl,    carboxyethyl, C₁-C₄-alkoxycarbonyl-C₁-C₆-alkyl, in particular    methoxycarbonylmethyl, ethoxycarbonylethyl,    C₁-C₄-aryl-alkoxycarbonyl-C₁-C₆-alkyl, in particular    benzyloxycarbonylmethyl, C₁-C₄-alkylamino-C₁-C₆-alkyl, in particular    methylaminopropyl, methylaminobutyl, C₁-C₄-dialkylamino-C₁-C₆-alkyl,    in particular dimethylaminopropyl, dimethylaminobutyl,    C₂-C₆-alkenyl, in particular vinyl, allyl, butenyl,    C₃-C₇-cycloalkyl, in particular cyclopentyl, cyclohexyl,    cycloheptyl, C₃-C₇-cycloalkyl-C₁-C₄-alkyl, in particular    cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, phenyl,    phenyl-C₁-C₄-alkyl, in particular phenylmethyl which can optionally    be substituted by one or more identical or different radicals from    amongst those stated above, and their optical isomers and racemates.

Very especially preferred are compounds of the formula (I),

in which

-   R¹, R³ and R⁵ independently of one another represent straight-chain    or branched C₁-C₈-alkyl, in particular methyl, ethyl, propyl,    isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl,    sec-pentyl, hexyl, isohexyl, sec-hexyl, heptyl, isoheptyl,    sec-heptyl, octyl, isooctyl, sec-octyl, C₂-C₈-alkenyl, in particular    allyl, C₃-C₇-cycloalkyl-C₁-C₄-alkyl, in particular cyclohexylmethyl,    phenyl-C₁-C₄-alkyl, in particular phenylmethyl,-   R², R⁴ and R⁶ independently of one another represent straight-chain    or branched C₁-C₈-alkyl, in particular methyl, ethyl, propyl,    isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl,    sec-pentyl, hexyl, isohexyl, sec-hexyl, heptyl, isoheptyl,    sec-heptyl, octyl, isooctyl, sec-octyl, C₂-C₈-alkenyl, in particular    vinyl, allyl, C₃-C₇-cycloalkyl-C₁-C₄-alkyl, in particular    cyclohexylmethyl, phenyl-C₁-C₄-alkyl, in particular phenylmethyl    which can optionally be substituted by one or more identical or    different radicals from amongst those stated above,    -   and their optical isomers and racemates.

All compounds of the general formula (I) which can exist in opticallyactive, stereoisomeric forms or as racemic mixtures can be used for thepurposes of the present invention. However, it is preferred inaccordance with the invention to use the optically active,stereoisomeric forms of the compounds of the general formula (I).

The following compounds of the general formula (I) in which

-   the radicals R¹ to R⁶ have the meanings stated hereinbelow-   may be mentioned individually:

(I)

R¹ R² R³ R⁴ R⁵ R⁶ —CHMeCH₂Me -cyclohexyl —CHMeCH₂Me —Me —CHMeCH₂Me —Me—CHMeCH₂Me -cyclohexyl —CHMeCH₂Me —Me —CHMeCH₂Me -cyclohexyl —CHMeCH₂Me—CH₂—Phe —CHMeCH₂Me —Me —CHMeCH₂Me —Me —CHMeCH₂Me —CH₂—Phe —CHMeCH₂Me—Me —CHMeCH₂Me —CH₂—Phe —CHMeCH₂Me —(CH₂)₃—Me —CHMeCH₂Me —Me —CHMeCH₂Me—Me —CHMeCH₂Me —(CH₂)₃—Me —CHMeCH₂Me —Me —CHMeCH₂Me —(CH₂)₃—Me —CHMe₂—CH₂—Phe —CHMeCH₂Me —Me —CHMeCH₂Me —Me —CH₂—Phe —CHMe₂ —CH₂—Phe —CHMe₂—CHMeCH₂Me —CHMe₂ —CH₂CHMe₂ —CH₂—Phe —CH₂CHMe₂ —Me —CH₂CHMe₂ —CH₂—Phe—(CH₂)₃—Me —Me —CHMeCH₂Me —Me —CHMeCH₂Me —Me —CHMe₂ —Me —CHMe₂ —Me—CHMe₂ —Me —CH₂—Me —Me —CH₂—Me —Me —CH₂—Me —Me —(CH₂)₂—Me —Me —(CH₂)₂—Me—Me —(CH₂)₂—Me —Me —(CH₂)₃—Me —Me —(CH₂)₃—Me —Me —(CH₂)₃—Me —Me—CH₂—CH═CH₂ —Me —CH₂—CH═CH₂ —Me —(CH₂)—CH═CH₂ —Me —CHMeCH₂Me —Me—CHMeCH₂Me —Me —CHMeCH₂Me —CH₂—Me —CHMeCH₂Me —Me —CHMeCH₂Me —Me—CHMeCH₂Me —(CH₂)₂—Me —CHMeCH₂Me —Me —CHMeCH₂Me —Me —CHMeCH₂Me—(CH₂)₃—Me —CHMeCH₂Me —Me —CHMeCH₂Me —Me —CH₂Me —Me —CHMeCH₂Me —Me—CHMeCH₂Me —Me —(CH₂)₂—Me —Me -cyclohexyl —Me -cyclohexyl —Me-cyclohexyl —Me —CH₂CHMe₂ -cyclohexyl —CH₂CHMe₂ —Me —CH₂CHMe₂-cyclohexyl —CH₂CHMe₂ -cyclohexyl —CH₂CHMe₂ —Me —CH₂CHMe₂ —Me —CHMeCH₂Me—CHMe₂ —CHMeCH₂Me —CHMe₂ —CHMeCH₂Me —Me —CH₂—Phe —Me —CH₂—Phe —Me—CH₂—Phe —Me -cyclohexyl —Me -cyclohexyl —Me -cyclohexyl —Me —CHMe₂—CHMe₂ —CHMe —Me —CHMe₂ —Me —CHMe₂ —CHMe₂ —CHMe₂ —CHMe₂ —CHMe₂ —Me—CH₂—Me —CHMe₂ —CH₂Me —Me —CH₂—Me —Me —CH₂—Me —CHMe₂ —CHMe₂ —CHMe₂—CH₂—Me —Me —(CH₂)₂—Me —CHMe₂ —(CH₂)₂—Me —Me —(CH₂)₂—Me —Me —(CH₂)₂—Me—CHMe₂ —(CH₂)₂—Me —CHMe₂ —(CH₂)₂—Me —Me —(CH₂)₃—Me —CHMe₂ —(CH₂)₃—Me —Me—(CH₂)₃—Me —Me —(CH₂)₃—Me —CHMe₂ —(CH₂)₃—Me —CHMe₂ —(CH₂)₃—Me —Me—CH₂—CH═CH₂ —CHMe₂ —CH₂—CH═CH₂ —Me —CH₂—CH═CH₂ —Me —CH₂—CH═CH₂ —CHMe₂—CH₂—CH═CH₂ —CHMe₂ —CH₂—CH═CH₂ —Me —Me —Me —CHMeCH₂Me —Me —CH₂—Me —Me—Me —Me —CHMeCH₂Me —Me —(CH₂)₃—Me —Me Me = methyl; Phe = phenyl

A further depsipeptide which may be mentioned is the compound PF 1022,which is disclosed in EP-OS 382 173 and has the following formula:

Moreover, depsipeptides which may be mentioned are the compoundsdisclosed in PCT Application WO 93/19053.

Compounds from PCT Application WO 93/19053 which may be mentioned inparticular are those of the following formula:

in which

-   z represents N-morpholinyl, amino, mono- or dimethylamino.

An especially preferred example of these compounds is the bis-morpholinoderivativecyclo[D-2-hydroxypropanoyl-N-methyl-L-leucyl-3-[4-(4-morpholinyl)phenyl]-D-2-hydroxypropanoyl-N-methyl-L-leucyl-D-2-hydroxypropanoyl-N-methyl-L-leucyl-3[4-(4-morpholinyl)phenyl]-D-2-hydroxypropanoyl-N-methyl-L-leucyl](CAS 155030-63-0).

Compounds which may additionally be mentioned are those of the followingformula:

in which

-   R¹, R², R³, R⁴ independently of one another represent hydrogen,    C₁-C₁₀-alkyl or aryl, in particular phenyl, which are optionally    substituted by hydroxyl, C₁-C₁₀-alkoxy or halogen.

The compounds of the general formula (I) are known and can be obtainedby the processes described in EP-A-382 173, DE-A 4 317 432, DE-A 4 317457, DE-A 4 317458, EP-A-634 408, EP-A-718 293, EP-A-872 481, EP-A-685469, EP-A-626 375, EP-A-664 297, EP-A-669 343, EP-A-787 141, EP-A-865498, EP-A-903 347.

The cyclic depsipeptides having 24 ring atoms also include compounds ofthe general formula (Ia)

in which

-   R^(1a), R^(2a), R^(11a) and R^(12a) independently of one another    represent C₁₋₈-alkyl, C₁₋₈-halogenoalkyl, C₃₋₆-cycloalkyl, aralkyl,    aryl,-   R^(3a), R^(5a), R^(7a), R^(9a) independently of one another    represent hydrogen or straight-chain or branched C₁₋₈-alkyl which    can optionally be substituted by hydroxyl,

-    guanidino, —SH or C₁₋₄-alkylthio, and furthermore represent aryl or    aralkyl, each of which can be substituted by halogen, hydroxyl,    C₁₋₄-alkyl, C₁₋₄-alkoxy,-   R^(4a), R^(6a), R^(8a), R^(10a) independently of one another    represent hydrogen, or represent straight-chain C₁₋₅-alkyl,    C₂₋₆-alkenyl, C₃₋₇-cycloalkyl, each of which can optionally be    substituted by hydroxyl, C₁₋₄-alkoxy, carboxyl, carboxamide,    imidazolyl, indolyl, guanidino, SH or C₁₋₄-alkylthio, and represent    aryl or aralkyl, each of which can be substituted by halogen,    hydroxyl, C₁₋₄-alkyl, C₁₋₄-alkoxy,    -   and their optical isomers and racemates.

Compounds of the formula (Ia) which are preferably employed are those inwhich

-   R^(1a), R^(2a), R^(11a) and R^(12a) independently of one another    represent methyl, ethyl, propyl, isopropyl, n-, s-, t-butyl or    phenyl, which is optionally substituted by halogen, C₁₋₄-alkyl, OH,    C₁₋₄-alkoxy, and represent benzyl or phenylethyl, each of which can    optionally be substituted by the radicals stated for phenyl;-   R^(3a) to R^(10a) have the abovementioned meaning.

Especially preferred compounds of the formula (Ia) are those in which

-   R^(1a), R^(2a), R^(11a) and R^(12a) independently of one another    represent methyl, ethyl, propyl, isopropyl or n-, s-, t-butyl,-   R^(3a), R^(5a), R^(7a), R^(9a) represent hydrogen, or represent    straight-chain or branched C₁₋₈-alkyl, in particular methyl, ethyl,    propyl, i-propyl, n-, s-, t-butyl, each of which can optionally be    substituted by C₁₋₄-alkoxy, in particular methoxy, ethoxy,    imidazolyl, indolyl or C₁₋₄-alkylthio, in particular methylthio,    ethylthio, furthermore represent phenyl, benzyl or phenethyl, each    of which can optionally be substituted by halogen, in particular    chlorine,-   R^(4a), R^(6a), R^(8a), R^(10a) independently of one another    represent hydrogen, or represent methyl, ethyl, n-propyl, n-butyl,    vinyl, cyclohexyl, each of which can optionally be substituted by    methoxy, ethoxy, imidazolyl, indolyl, methylthio, ethylthio, and    represent isopropyl, s-butyl, and furthermore in each case    optionally halogen-substituted phenyl, benzyl or phenylethyl.

The compounds of the formula (Ia) can also be obtained by the processesdescribed in EP-A-382 173, DE-A 4 317 432, DE-A 4 317 457, DE-A 4 317458, EP-A-634 408, EP-A-718 293, EP-A-872 481, EP-A-685 469, EP-A-626375, EP-A-664 297, EP-A-669 343, EP-A-787 141, EP-A-865 498, EP-A-903347.

The compositions according to the invention are suitable for controllingpathogenic endoparasites found in humans and in animal keeping andlivestock breeding in productive livestock, breeding animals, zooanimals, laboratory animals, experimental animals and pets while havingfavourable toxicity to warm-blooded species. They are active against allor individual developmental stages of the pests and against resistantand normally sensitive species. By controlling the pathogenicendoparasites, it is intended to reduce disease, death and reducedperformance (for example in the production of meat, milk, wool, hides,eggs, honey and the like), so that more economical and simpler animalkeeping is possible by using the active compounds. The pathogenicendoparasites include cestodes, trematodes, nematodes, acantocephala, inparticular:

From the order of the Pseudophyllidea, for example: Diphyllobothriumspp., Spirometra spp., Schistocephalus spp., Ligula spp., Bothridiumspp., Diphlogonoporus spp.

From the order of the Cyclophyllidea, for example: Mesocestoides spp.,Anoplocephala spp., Paranoplocephala spp., Moniezia spp., Thysanosomsaspp., Thysaniezia spp., Avitellina spp., Stilesia spp., Cittotaeniaspp., Andyra spp., Bertiella spp., Taenia spp., Echinococcus spp.,Hydatigera spp., Davainea spp., Raillietina spp., Hymenolepis spp.,Echinolepis spp., Echinocotyle spp., Diorchis spp., Dipylidium spp.,Joyeuxiella spp., Diplopylidium spp.

From the sub-class of the Monogenea, for example: Gyrodactylus spp.,Dactylogyrus spp., Polystoma spp.

From the sub-class of the Digenea, for example: Diplostomum spp.,Posthodiplostomum spp., Schistosoma spp., Trichobilharzia spp.,Ornithobilharzia spp., Austrobilharzia spp., Gigantobilharzia spp.,Leucochloridium spp., Brachylaima spp., Echinostoma spp.,Echinoparyphium spp., Echinochasmus spp., Hypoderaeum spp., Fasciolaspp., Fasciolides spp., Fasciolopsis spp., Cyclocoelum spp.,Typhlocoelum spp., Paramphistomum spp., Calicophoron spp-, Cotylophoronspp., Gigantocotyle spp., Fischoederius spp., Gastrothylacus spp.,Notocotylus spp., Catatropis spp., Plagiorchis spp., Prosthogonimusspp., Dicrocoelium spp., Eurytrema spp., Troglotrema spp., Paragonimusspp., Collyriclum spp., Nanophyetus spp., Opisthorchis spp., Clonorchisspp. Metorchis spp., Heterophyes spp., Metagonimus spp.

From the order of the Enoplida, for example: Trichuris spp., Capillariaspp., Trichomosoides spp., Trichinella spp.

From the order of the Rhabditia, for example: Micronema spp.,Strongyloides spp.

From the order of the Strongylida, for example: Stronylus spp.,Triodontophorus spp., Oesophagodontus spp., Trichonema spp.,Gyalocephalus spp., Cylindropharynx spp., Poteriostomum spp.,Cyclococercus spp., Cylicostephanus spp., Oesophagostomum spp.,Chabertia spp., Stephanurus spp., Ancylostoma spp., Uncinaria spp.,Bunostomum spp.,

Globocephalus spp., Syngamus spp., Cyathostoma spp., Metastrongylusspp., Dictyocaulus spp., Muellerius spp., protostrongylus spp.,Neostrongylus spp., Cystocaulus spp., Pneumostrongylus spp., Spicocaulusspp., Elaphostrongylus spp. Parelaphostrongylus spp., Crenosoma spp.,Paracrenosoma spp., Angiostrongylus spp., Aelurostrongylus spp.,Filaroides spp., Parafilaroides spp., Trichostrongylus spp., Haemonchusspp., Ostertagia spp., Marshallagia spp., Cooperia spp., Nematodirusspp., Hyostrongylus spp., Obeliscoides spp., Amidostomum spp., Ollulanusspp.

From the order of the Oxyurida, for example: Oxyuris spp., Enterobiusspp., Passalurus spp., Syphacia spp., Aspiculuris spp., Heterakis spp.

From the order of the Ascaridia, for example: Ascaris spp., Toxascarisspp., Toxocara spp., Parascaris spp., Anisakis spp., Ascaridia spp.

From the order of the Spirurida, for example: Gnathostoma spp.,Physaloptera spp., Thelazia spp., Gongylonema spp., Habronema spp.,Parabronema spp., Draschia spp., Dracunculus spp.

From the order of the Filariida, for example: Stephanofilaria spp.,Parafilaria spp., Setaria spp., Loa spp., Dirofilaria spp., Litomosoidesspp., Brugia spp., Wuchereria spp., Onchocerca spp.

From the order of the Gigantorhynchida, for example: Filicollis spp.,Moniliformis spp., Macracanthorhynchus spp., Prosthenorchis spp.

Other productive livestock are breeding animals including mammals suchas, for example, cattle, horses, sheep, pigs, goats, camels, waterbuffaloes, donkeys, rabbits, fallow deer, reindeer, fur bearers such as,for example, mink, chinchilla and racoon, birds such as, for example,chickens, geese, turkeys, ducks and ostriches, fresh water and saltwater fish such as, for example, trout, salmon, carp and eels, reptiles,and insects such as, for example, honeybee and silkworm.

Laboratory animals and experimental animals include mice, rats, guineapigs, golden hamsters, dogs and cats.

The pets include dogs and cats.

The compositions according to the invention are particularly preferablyemployed in dogs and cats, in particular dogs.

Application can be effected both prophylactically and therapeutically.

The shaped articles according to the invention can also be used ascarriers for the administration of other active compounds. Exampleswhich may be mentioned are: other active compounds which act againstpathogenic endoparasites such as, for example,L-2,3,5,6-tetrahydro-6-phenylimidazothiazole, benzimidazolecarbamatessuch as febantel, furthermore pyrantel, praziquantel and ivermectin;coccidiostats such as toltrazuril and ponazuril (=toltrazuril-sulphone);painkillers such as flupirtin and antibiotics such as enrofloxacin, andthe compounds described in WO 97/31001, in particular8-cyano-1-cyclopropyl-7-((1S,6S)-2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid of the formula

In the shaped articles according to the invention, the active compoundscan also be employed in combination with synergists or with othersuitable active compounds. For example, the depsipeptides stated furtherabove can be combined with other active compounds against pathogenicendoparasites, for example those which have been mentioned furtherabove.

Ready-for-use preparations comprise the active compounds inconcentrations from 10 ppm-25 percent by weight, preferably 0.1-20percent by weight.

To achieve effective results, it has generally proved advantageous toadminister amounts of the mixture according to the invention ofapproximately 0.001 to approximately 100 mg of active compound per kg ofbodyweight per day. Preferred are 0.005 to 5 mg of active compound perkg of bodyweight.

Ancillairy substances which are used are: starch such as, for example,starch from wheat, rice, maize, tapioca, rye, oats and potatoes.Modified starches can be physically pretreated starches such aspregelatinized or chemically modified starches such ashydroxyethylstarch, hydroxypropylstarch, methylstarch,carboxymethylstarch, starch acetate, hydroxypropylstarch acetate,hydroxyethylstarch acetate, starch phosphates, starch sulphates, orchemically or ionically crosslinked starches such as dye-starchphosphates, phosphates of hydroxypropylated starches, starchdicarboxylic acid diesters or salts of anionic starch derivatives.Preferred are hydroxypropylated and phosphate-crosslinked starches ofmaize, wheat, tapioca and potato. Starch quantities of between 30% and80%, preferably between 40% and 70%, especially preferably between 40and 60%, are employed in this context. The percentages are percent byweight of the finished composition.

Sugars such as sucrose, glucose, fructose, mannose and sorbitol arefurthermore used. Quantities of between 1% and 20%, preferably between1% and 15%, especially preferably between 1% and 10%, are employed inthis context. The percentages are percent by weight of the finishedcomposition.

Materials which are especially suitable for shaping and bodying arecellulose and its derivatives such as microcrystalline cellulose,hydroxypropylcellulose, methylhydroxypropylcellulose,carboxymethylcellulose, especially cellulose acetate and very especiallycellulose-2,5-acetate. Materials which are furthermore suitable arehighly-dispersed silicates and titanium dioxide. Amounts of between 1%and 40%, preferably between 1% and 30%, especially preferably between 1and 20%, are employed in this context. The percentages are percent byweight of the finished composition.

Materials which act as humectants and plasticizers are water, glycerol,propylene glycol, polyethylene glycols and polypropylene glycols.Amounts of between 1% and 30%, preferably between 5% and 30%, especiallypreferably between 5 and 20%, are employed in this context. Thepercentages are percent by weight of the finished composition.

Preservatives which can be employed are compounds conventionally usedfor pharmaceutical preparations and foodstuffs, such as benzoic esters,methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, propylp-hydroxybenzoate, sorbic acid, propyl gallate, citric acid, ascorbicacid, ascorbin palmitate, tocopherol, tocopherol acetate,butylhydroxytoluene and butylhydroxyanisole.

Emulsifiers which can be employed are: surfactants such as

-   1. nonionic surfactants, for example polyoxyethylated castor oil,    polyoxyethylated sorbitan monooleate, sorbitan monostearate, ethyl    alcohol, glycerol monostearate, polyoxyethyl stearate, alkylphenol    polylglycol ethers,-   2. ampholytic surfactants, such as disodium    N-lauryl-B-iminodipropionate or lecithin,-   3. anionic surfactants, such as sodium lauryl sulphate, fatty    alcohol ether sulphates, mono/dialkyl polyglycol ether    orthophosphoric ester monoethanolamine salt.

The quantities employed here preferably amount to 0.05% by weight to 2%by weight, based on the total amount of constituents. Quantities of from0.2 to 1% by weight are especially preferred.

Ideally, the shaped articles according to the invention have a Shore Ahardness of 10 to 100, preferably 10 to 65, very especially preferably10 to 30, in particular 15 to 25. The Shore A hardness is determined asspecified by DIN Method 53505.

Suitable aromas are powdered liver from cattle, poultry, sheep or pigs,preferably poultry and pigs, and other aroma preparations. Amounts ofbetween 1% and 30%, preferably between 5% and 25%, especially preferablybetween 5% and 20%, are employed in this context. The percentages arepercent by weight of the finished composition.

Very especially suitable are the aromas which are commerically availablefrom Pharmachem (BEEF®) and Haarmann und Reimer (BAYOPAL®) under thenames BEEF® and BAYOPAL®.

The examples which follow illustrate the invention without imposing anylimitation. The active compound employed in the examples is the compoundcyclo[D-2-hydroxypropanoyl-N-methyl-L-leucyl-3-[4-(4-morpholinyl)phenyl]-D-2-hydroxypropanoyl-N-methyl-L-leucyl-D-2-hydroxypropanoyl-N-methyl-L-leucyl-3[4-(4-morpholinyl)phenyl]-D-2-hydroxypropanoyl-N-methyl-L-leucyl] (CAS155030-63-0).

BRIEF DESCRIPTION OF THE DRAWING

The FIGURE shows the acceptance of the placebo and the verum samples asdetailed in Example 3.

EXAMPLE 1

55% of wheat flour, 10% of fructose, 10% of beef aroma, Pharma-Chemie,1% of Aerosil and 4% of depsipeptide are homogenized and screened andthe mixture is subsequently fed to an extruder via a measuring screw.Accordingly, 5% of water and 15% of glycerol (based on the totalmixture) are pumped in via a metering pump. The extrusion temperature is120° C. The extrudate formed is cut into pieces so that one piececontains the dose for 10 kg of the animal's bodyweight. The percentageshere are to be understood as percent by weight.

EXAMPLE 2

45% of cornstarch, 10% of sucrose, 10% of liver aroma, Haarmann &Reimer, 10% of cellulose acetate powder, 1% of Aerosil and 4% ofdepsipeptide are homogenized and screened and the mixture issubsequently fed to an extruder via a measuring screw. Accordingly, 5%of water and 15% of glycerol (based on the total mixture) are pumped invia a metering pump. The extrusion temperature is 120° C. The extrudateformed is cut into pieces so that one piece contains the dose for 10 kgof the animal's bodyweight. The percentages here are to be understood aspercent by weight.

EXAMPLE 3

The samples prepared in Example 2 are fed to dogs. Both placebo sample(without active compound) and verum sample (with active compound) aretested against a commercially available food which contains meat(“Frolic”). The acceptance of the placebo and the verum samples iscomparable as shown in the FIGURE.

EXAMPLE 4

The samples of Example 1 or 2 are fed to parasite-infected dogs at adosage of 5 mg of depsipeptide per kg of bodyweight. After two to fourdays, the animals are free of parasites.

Animal Parasite Effect 2 dogs Toxocara canis 3/3 2 dogs Ancylostomacaninum 3/3

1. A starched-based extruded shaped article which has a Shore A hardnessof 10 to 100, characterized in that the article comprises a combinationof one or more specific aromas, one or more bodying agents and one ormore pharmaceutically active compounds for animals.
 2. Starch-basedextruded shaped articles according to claim 1, wherein the aroma isselected from the group consisting of poultry liver aroma and meataroma.
 3. Starch-based extruded shaped articles according to claim 1,wherein the pharmaceutically active compound is a cyclic depsipeptidescomposed of amino acids and hydrocarboxylic acids as units and having 6to 30 ring or chain atoms.
 4. Starch-based extruded shaped articlesaccording to claim 1, further comprising pulverulent cellulose acetate.5. Starch-based extruded shaped articles according to claim 1, furthercomprising ancillary materials selected from the group consisting ofemulsifiers, humectants and preservatives.
 6. Process for thepreparation of starch-based extruded shaped articles according to claim1, wherein the aroma, bodying agent, and pharmaceutically activecompound are mixed and processed at extrusion temperatures of less than150° C.
 7. Starch-based extruded shaped articles according to claim 2,wherein the pharmaceutically active compound is a cyclic depsipeptidescomposed of amino acids and hydroxycarboxylic acids as units and having6 to 30 ring or chain atoms.
 8. Starch-based extruded shaped articlesaccording to claim 2, further comprising pulverulent cellulose acetate.9. Starch-based extruded shaped articles according to claim 2, furthercomprising ancillary materials selected from the group consisting ofemulsifier, humectants, and preservatives.
 10. Starch-based extrudedshaped articles according to claim 3, further comprising ancillarymaterials selected from the group consisting of emulsifiers, humectants,and preservatives.
 11. Process for the preparation of starch-basedextruded shaped articles according to claim 2, wherein the aroma,bodying agent, and pharmaceutically active compound are mixed andprocessed at extrusion temperatures of less than 150° C.
 12. Process forthe preparation of starch-based extruded shaped articles according toclaim 3, wherein the aroma, bodying agent, and pharmaceutically activecompound are mixed and processed at extrusion temperatures of less than150° C.
 13. A starched-based extruded shaped article, characterized inthat the article comprises a combination of one or more specific aromas,one or more bodying agents and one or more cyclic depsipeptide composedof amino acids and hydrocarboxylic acids as units and having 6 to 30ring or chain atoms and wherein the shaped article has a Shore Ahardness of 10 to
 65. 14. A starched-based extruded shaped article whichhas a Shore A hardness of 10 to 100, characterized in that the articlecomprises a combination of one or more specific aromas, one or morebodying agents and one or more cyclic depsipeptide composed of aminoacids and hydrocarboxylic acids as units and having 6 to 30 ring orchain atoms, wherein the aroma, bodying agent, and cyclic depsipeptideare mixed and processed at extrusion temperatures of less than 150° C.